Increased fetal hemoglobin (HbF) in cells of patients with beta- hemoglobinopathies (beta-thalassemia and sickle cell anemia) ameliorates the clinical symptoms of the underlying disease. Recently, several pharmacologic agents have been used to stimulate HbF synthesis; e.g., treatment of patients with hydroxyurea resulted in higher HbF levels and a significant improvement in the clinical symptoms. Yet, there is a considerable interest in other less toxic agents with expanded or higher potential to increase HbF. So far only a handful of agents have been tested, mainly due to the lack of an appropriate experimental system that allows a rapid and accurate determination of the effect on relevant cells. We have recently developed a two-phase liquid culture system for growing erythroid progenitors derived form the peripheral blood of normal individuals and patients with hemoglobinopathies. We showed that the system recapitulates many aspects of erythropoiesis in vivo , including stimulation of HbF production by pharmacologic agents. The purpose of our research is to utilize this culture procedure and various biochemical, molecular and immunological methods developed by us lately, to study the regulation of Hb production and for screening of agents for their HbF- stimulating potential with the final objective to produce an efficient, low toxicity therapy. The experiments include optimization of the conditions for stimulation of HbF production, followed by screening of various agents and subsequently studying their mode(s) of action. We have recently found that hemin, and hemin-hydroxyurea combinations, markedly increase HbF in these cells. We are now studying the effects of these drugs in non-human primates. We are also working with Oncogene Sciences, Inc. which has developed a robotic system for screening large numbers of compounds which may affect globin gene transcription. We are testing the compounds which score positively in this system in our culture system. We hope that our studies will facilitate the discovery of new compounds or combinations of drugs that will be clinically useful.